The purpose of this study was to characterise the biomechanical properties of the seven hole superior anterior clavicle LCP (locking compression plate) and to compare these with the properties of commonly applied implants used for the stabilisation of clavicular midshaft fractures such as the locking 7- and ten hole reconstruction plate.
Twenty-four synthetic clavicles were used. A transverse midshaft fracture was induced. The clavicles were fixed with angle stable clavicle LCPs, seven hole and ten hole reconstruction plates (n = 8 each). Twenty cycles of axial compression and torsion were performed for each sample, which was followed by 1,000 cycles of three point bending and ultimately bending to failure. Axial, torsional and cantilever bending stiffness were calculated from the data recorded.
The clavicle LCP showed the highest overall stiffness compared to the seven and ten hole reconstruction plate. Significantly higher stiffness values were found for axial compression and external rotation. In the load-to-failure tests, the ten hole reconstruction plate especially showed early signs of plastic deformation, which might account for early plate insufficiency so frequently observed clinically.
The results indicate that the clavicle LCP, as compared to the reconstruction plates, leads to superior biomechanical stability in the treatment of midshaft clavicle fractures.
Norovirus (NoV) is the leading cause of viral gastroenteritis globally. Since 1996, NoV variants of a single genetic lineage, GII.4, have been associated with at least six pandemics of acute gastroenteritis and caused between 62 and 80% of all NoV outbreaks. The emergence of these novel GII.4 variants has been attributed to rapid evolution and antigenic variation in response to herd immunity; however, the contribution of recombination as a mechanism facilitating emergence is increasingly evident. In this study, we sought to examine the role that intragenotype recombination has played in the emergence of GII.4 variants. Using a genome-wide approach including 25 complete genome sequences generated as part of this study, 11 breakpoints were identified within the NoV GII.4 lineage. The breakpoints were located at three recombination hot spots: near the open reading frame 1/2 (ORF1/2) and ORF2/3 overlaps, as well as within ORF2, which encodes the viral capsid, at the junction of the shell and protruding domains. Importantly, we show that recombination contributed to the emergence of the recent pandemic GII.4 variant, New Orleans 2009, and a newly identified GII.4 variant, termed Sydney 2012. Reconstructing the evolutionary history of the GII.4 lineage reveals the widespread impact of both inter- and intragenotype recombination on the emergence of many GII.4 variants. Lastly, this study highlights the many challenges in the identification of true recombination events and proposes that guidelines be applied for identifying NoV recombinants.
Anergy is a key physiological mechanism for restraining self-reactive B cells. A marked portion of peripheral B cells are anergic B cells that largely depend on B cell-activating factor (BAFF) for survival. BAFF activates the canonical and noncanonical NF-κB pathways, both of which are required for B cell survival. Here we report that deficiency of the adaptor protein B cell lymphoma 10 (Bcl10) impaired the ability of BAFF to support B cell survival in vitro, and specifically increased apoptosis in anergic B cells in vivo, dramatically reducing anergic B cells in mice. Bcl10-dependent survival of self-reactive anergic B cells was confirmed in the IgHELsHEL double-transgenic mouse model of B cell anergy. Further, we found that BAFF stimulation induced Bcl10 association with IKKβ, a key component of the canonical NF-κB pathway. Consistently, Bcl10-deficient B cells were impaired in BAFF-induced IκBα phosphorylation and formation of nuclear p50:c-Rel complexes. Bcl10-deficient B cells also displayed reduced expression of NF-κB2/p100, severely reducing BAFF-induced nuclear accumulation of noncanonical p52:RelB complexes. Consequently, Bcl10-deficient B cells failed to express Bcl-xL, a BAFF-induced NF-κB target gene. Taken together, these data demonstrate that Bcl10 controls BAFF-induced canonical NF-κB activation directly and noncanonical NF-κB activation indirectly. The BAFF-R/Bcl10/NF-κB signaling axis plays a critical role in peripheral B cell tolerance by regulating the survival of self-reactive anergic B cells.
BAFF; Bcl10; NF-κB; apoptosis; anergic B cells; tolerance
We have previously demonstrated that quercetin, a bioflavonoid, blocks hepatitis C virus (HCV) proliferation by inhibiting NS5A-driven internal ribosomal entry site (IRES)-mediated translation of the viral genome. Here, we investigate the mechanisms of antiviral activity of quercetin and six additional bioflavonoids. We demonstrate that catechin, naringenin, and quercetin possess significant antiviral activity, with no associated cytotoxicity. Infectious virion secretion was not significantly altered by these bioflavonoids. Catechin and naringenin demonstrated stronger inhibition of infectious virion assembly compared to quercetin. Quercetin markedly blocked viral translation whereas catechin and naringenin demonstrated mild activity. Similarly quercetin completely blocked NS5A-augmented IRES-mediated translation in an IRES reporter assay, whereas catechin and naringenin had only a mild effect. Moreover, quercetin differentially inhibited HSP70 induction compared to catechin and naringenin. Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV.
HSP70; NS5A; IRES; HCV; Bioflavonoid
The Caribbean basin is home to some of the most complex interactions in recent history among previously diverged human populations. Here, we investigate the population genetic history of this region by characterizing patterns of genome-wide variation among 330 individuals from three of the Greater Antilles (Cuba, Puerto Rico, Hispaniola), two mainland (Honduras, Colombia), and three Native South American (Yukpa, Bari, and Warao) populations. We combine these data with a unique database of genomic variation in over 3,000 individuals from diverse European, African, and Native American populations. We use local ancestry inference and tract length distributions to test different demographic scenarios for the pre- and post-colonial history of the region. We develop a novel ancestry-specific PCA (ASPCA) method to reconstruct the sub-continental origin of Native American, European, and African haplotypes from admixed genomes. We find that the most likely source of the indigenous ancestry in Caribbean islanders is a Native South American component shared among inland Amazonian tribes, Central America, and the Yucatan peninsula, suggesting extensive gene flow across the Caribbean in pre-Columbian times. We find evidence of two pulses of African migration. The first pulse—which today is reflected by shorter, older ancestry tracts—consists of a genetic component more similar to coastal West African regions involved in early stages of the trans-Atlantic slave trade. The second pulse—reflected by longer, younger tracts—is more similar to present-day West-Central African populations, supporting historical records of later transatlantic deportation. Surprisingly, we also identify a Latino-specific European component that has significantly diverged from its parental Iberian source populations, presumably as a result of small European founder population size. We demonstrate that the ancestral components in admixed genomes can be traced back to distinct sub-continental source populations with far greater resolution than previously thought, even when limited pre-Columbian Caribbean haplotypes have survived.
Latinos are often regarded as a single heterogeneous group, whose complex variation is not fully appreciated in several social, demographic, and biomedical contexts. By making use of genomic data, we characterize ancestral components of Caribbean populations on a sub-continental level and unveil fine-scale patterns of population structure distinguishing insular from mainland Caribbean populations as well as from other Hispanic/Latino groups. We provide genetic evidence for an inland South American origin of the Native American component in island populations and for extensive pre-Columbian gene flow across the Caribbean basin. The Caribbean-derived European component shows significant differentiation from parental Iberian populations, presumably as a result of founder effects during the colonization of the New World. Based on demographic models, we reconstruct the complex population history of the Caribbean since the onset of continental admixture. We find that insular populations are best modeled as mixtures absorbing two pulses of African migrants, coinciding with the early and maximum activity stages of the transatlantic slave trade. These two pulses appear to have originated in different regions within West Africa, imprinting two distinguishable signatures on present-day Afro-Caribbean genomes and shedding light on the genetic impact of the slave trade in the Caribbean.
Placement of deep brain stimulating electrodes in the subthalamic nucleus (STN) to treat Parkinson’s disease (PD) also allows the recording of single neuron spiking activity. Analyses of these unique data offer an important opportunity to better understand the pathophysiology of PD. Despite the point process nature of PD neural spiking activity, point processmethods are rarely used to analyze these recordings. We develop a point process representation of PD neural spiking activity using a generalized linear model to describe long- and short-term temporal dependencies in the spiking activity of 28 STN neurons from seven PD patients and 35 neurons from one healthy primate (surrogate control) recorded, while the subjects executed a directed-hand movement task. We used the point process model to characterize each neuron’s bursting, oscillatory, and directional tuning properties during key periods in the task trial. Relative to the control neurons, the PD neurons showed increased bursting, increased 10–30 Hz oscillations, and increased fluctuations in directional tuning. These features, which traditional methods failed to capture accurately, were efficiently summarized in a single model in the point process analysis of each neuron. The point process framework suggests a useful approach for developing quantitative neural correlates that may be related directly to the movement and behavioral disorders characteristic of PD.
Deep brain stimulation (DBS); Parkinson’s disease (PD); point processes; spike trains
Open fractures with severe soft-tissue trauma are predisposed to poor bone healing. The vital coupling between osteo- and angiogenesis is disturbed. Cysteine-rich protein 61 (CYR61) is an angiogenic inducer promoting vascularisation. However, little is known about the effect of CYR61 on the callus regenerate after acute musculoskeletal trauma. Therefore, our aim was to determine whether local administration of CYR61: (1) has an influence on callus formation and remodelling, (2) increases bone volume and (3) partially restores callus stability.
A musculoskeletal trauma was created in 20 rabbits. To simulate fracture-site debridement, the limb was shortened. In the test group, a CYR61-coated collagen matrix was locally applied around the osteotomy. After ten days, gradual distraction was commenced (0.5 mm/12 h) to restore the original length. New bone formation was evaluated histomorphometrically, radiographically and biomechanically.
Osseus consolidation occured in all animals. Average maximum callus diameter was higher in the test group [1.39 mm; standard deviation (SD) = 0.078 vs 1.26 mm (SD = 0.14); p = 0.096]. In addition, bone volume was higher (p = 0.11) in the test group, with a mean value of 49.73 % (SD = 13.68) compared with 37.6 % (SD = 5.91). Torsional strength was significantly higher (p = 0.005) in the test group [105.43 % (SD = 31.68 %) vs. 52.57 % (SD = 24.39)]. Instead, stiffness of the newly reconstructed callus decreased (64.21 % (SD = 11.52) vs. 71.30 % (SD = 32.25) (p = 0.81)).
CYR61 positively influences callus regenerate after acute trauma, not only histologically and radiographically but also biomechanically, most probably by a CYR61-associated pathway.
Entry of HIV-1 into target cells requires binding of the viral envelope glycoprotein (Env) to cellular receptors and subsequent conformational changes that culminates in fusion of viral and target cell membranes. Recent structural information has revealed that these conformational transitions are regulated by three conserved but potentially flexible layers stacked between the receptor-binding domain (gp120) and the fusion arm (gp41) of Env. We hypothesized that artificial insertion of a covalent bond will ‘snap’ Env into a conformation that is less mobile and stably expose conserved sites. Therefore, we analyzed the interface between these gp120 layers (layers 1, 2 and 3) and identified residues that may form disulfide bonds when substituted with cysteines. We subsequently probed the structures of the resultant mutant gp120 proteins by assaying their binding to a variety of ligands using Surface Plasmon Resonance (SPR) assay. We found that a single disulfide bond strategically inserted between the highly conserved layers 1 and 2 (C65-C115) is able to ‘lock’ gp120 in a CD4 receptor bound conformation (in the absence of CD4), as indicated by the lower dissociation constant (Kd) for the CD4-induced (CD4i) epitope binding 17b antibody. When disulfide-stabilized monomeric (gp120) and trimeric (gp140) Envs were used to immunize rabbits, they were found to elicit a higher proportion of antibodies directed against both CD4i and CD4 binding site epitopes than the wild-type proteins. These results demonstrate that structure-guided stabilization of inter-layer interactions within HIV-1 Env can be used to expose conserved epitopes and potentially overcome the sequence diversity of these molecules.
Amyloid fibrils are self-assembled protein aggregates implicated in a number of human diseases. Fragmentation-dominated models for the self-assembly of amyloid fibrils have had important successes in explaining the kinetics of amyloid fibril formation but predict fibril length distributions that do not match experiments. Here we resolve this inconsistency using a combination of experimental kinetic measurements and computer simulations. We provide evidence for a structural transition that occurs at a critical fibril mass concentration, or ‘CFC’, above which fragmentation of fibrils is suppressed. Our simulations predict the formation of distinct fibril length distributions above and below the CFC, which we confirm by electron microscopy. These results point to a new picture of amyloid fibril growth in which structural transitions that occur during self-assembly have strong effects on the final population of aggregate species with small, and potentially cytotoxic, oligomers dominating for long periods of time at protein concentrations below the CFC.
We sought to examine the efficacy and safety of acamprosate augmentation of escitalopram in patients with concurrent major depressive disorder (MDD) and alcohol use disorders. Twenty-three adults (43% female; mean ± SD age, 46 ± 14 years) were enrolled and received 12 weeks of treatment with psychosocial support; escitalopram, 10 to 30 mg/d; and either acamprosate, 2000 mg/d (n = 12), or identical placebo (n = 11). Outcomes included change in clinician ratings of depressive symptoms, MDD response and remission rates, changes in frequency and intensity of alcohol use, retention rates, and adverse events. Twelve subjects (acamprosate, n = 7; placebo, n = 5) completed the study. There was significant mean reduction in ratings of depressive symptoms from baseline in both treatment arms (P < 0.05), with no significant difference between the groups. Those in the acamprosate group had a 50% MDD response rate and a 42% remission rate, whereas those in the placebo arm had a 36% response and remission rate (not significant). Those assigned to acamprosate had significant reduction in number of drinks per week and drinks per month during the trial, whereas those assigned to placebo demonstrated no significant change in any alcohol use parameter, but the between-group difference was not significant. There were no significant associations between change in depressive symptoms and change in alcohol use. Attrition rates did not differ significantly between the 2 arms. Acamprosate added to escitalopram in adults with MDD and alcohol use disorders was associated with reduction in the frequency of alcohol use. The present study was not powered to detect superiority versus placebo. Further study in a larger sample is warranted.
acamprosate; alcohol use disorder; AUD; depression; MDD; escitalopram
The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) that first appeared in Saudi Arabia during the summer of 2012 has to date (20th September 2013) caused 58 human deaths. MERS-CoV utilizes the dipeptidyl peptidase 4 (DPP4) host cell receptor, and analysis of the long-term interaction between virus and receptor provides key information on the evolutionary events that lead to the viral emergence.
We show that bat DPP4 genes have been subject to significant adaptive evolution, suggestive of a long-term arms-race between bats and MERS related CoVs. In particular, we identify three positively selected residues in DPP4 that directly interact with the viral surface glycoprotein.
Our study suggests that the evolutionary lineage leading to MERS-CoV may have circulated in bats for a substantial time period.
MERS-CoV; Bats; Arms-race; Adaptive evolution; Emergence
This publication describes the history of Minimal Intervention Dentistry (MID) for managing dental caries and presents evidence for various carious lesion detection devices, for preventive measures, for restorative and non-restorative therapies as well as for repairing rather than replacing defective restorations. It is a follow-up to the FDI World Dental Federation publication on MID, of 2000. The dental profession currently is faced with an enormous task of how to manage the high burden of consequences of the caries process amongst the world population. If it is to manage carious lesion development and its progression, it should move away from the ‘surgical’ care approach and fully embrace the MID approach. The chance for MID to be successful is thought to be increased tremendously if dental caries is not considered an infectious but instead a behavioural disease with a bacterial component. Controlling the two main carious lesion development related behaviours, i.e. intake and frequency of fermentable sugars, to not more than five times daily and removing/disturbing dental plaque from all tooth surfaces using an effective fluoridated toothpaste twice daily, are the ingredients for reducing the burden of dental caries in many communities in the world. FDI’s policy of reducing the need for restorative therapy by placing an even greater emphasis on caries prevention than is currently done, is therefore, worth pursuing.
Minimal Intervention Dentistry; Caries lesion detection; Caries risk assessment; Caries preventive measures; restorative care; plaque control; repaired restoration
We investigated the activities and relevance of a validated panel of antioxidant enzymes, cytokines, specific lipid peroxidation end products and six fatty acids by correlational analyses with peak E2 levels and pregnancy outcome after ovarian stimulation for IVF or IUI.
Blood samples obtained from 15 patients undergoing ovarian stimulation with rFSH or hMG were divided into two groups. Group-1 was baseline blood collected on day-2-3 of women cycle. Group-2 is blood collected at the end of FSH/hMG injection. Serum was collected and stored in liquid nitrogen at -196 °C until analysis. Standard IVF and IUI procedures were followed. The serum levels of Paraoxonase (PON1), Superoxide Dismutases (SOD), Interleukin-6 (IL-6), Glutathione Peroxidase (GPx), 8-Isoprostane, and fatty acids Arachidic, Palmitic, Stearic, Oleic, Linoleic & Linolenic were measured.
With the exception of 8-Isoprostane, results showed a positive correlation between baseline and peak levels of E2 and that of SOD, GPx, PON1, and IL-6. The PON1, IL-6 and SOD were significantly (p < 0.05) higher in pregnant than non-pregnant group. Fatty acid levels at baseline and peak E2 were not different but pregnancy rates were found to be decreasing with higher palmitic, and stearic acid levels.
Ovarian stimulation causes a significant increase in serum PON1, SOD, GPx and IL-6 activity in women undergoing IVF or IUI. The high levels of IL-6, SOD, and PON1 and lower levels of palmitic, and stearic acids in the pregnancy positive group indicate that these oxidative stress and nutritional factors may be used as a predictive marker in controlled ovarian stimulation success.
Oxidative stress; Ovarian stimulation; IVF; IUI; Paraoxonase; Superoxide Dismutases; Interleukin-6; Glutathione Peroxidase; 8-Isoprostane; Fatty acids; Arachidic; Palmitic; Stearic; Oleic; Linoleic & Linolenic
The inhibitory protein SOCS3 plays a key role in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus Kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between murine SOCS3, JAK2 (kinase domain) and a fragment of the IL-6 receptor β-chain. The structure shows that SOCS3 binds JAK2 and receptor simultaneously, using two opposing surfaces. Whilst the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by receptor, JAK2 binds in a phospho-independent manner to a non-canonical surface. The kinase inhibitory region of SOCS3 occludes the substrate-binding groove on JAK2 and biochemical studies show it blocks substrate association. These studies reveal that SOCS3 targets specific JAK-cytokine receptor pairs and explains the mechanism and specificity of SOCS action.
Understanding the compatibility between spider silk and conducting materials is essential to advance the use of spider silk in electronic applications. Spider silk is tough, but becomes soft when exposed to water. Here we report a strong affinity of amine-functionalised multi-walled carbon nanotubes for spider silk, with coating assisted by a water and mechanical shear method. The nanotubes adhere uniformly and bond to the silk fibre surface to produce tough, custom-shaped, flexible and electrically conducting fibres after drying and contraction. The conductivity of coated silk fibres is reversibly sensitive to strain and humidity, leading to proof-of-concept sensor and actuator demonstrations.
The use of spider silk in electronic devices is dependent on its compatibility with electrically conductive materials. Here the authors modify spider silk with carbon nanotubes to produce a strong, flexible and electrically conductive thread.
To validate a diagnostic instrument for pediatric delirium in critically ill children, both ventilated and nonventilated, that uses standardized, developmentally appropriate measurements.
Design and Setting
A prospective observational cohort study investigating the Pediatric Confusion Assessment Method for Intensive Care Unit (pCAM-ICU) patients in the pediatric medical, surgical, and cardiac intensive care unit of a university-based medical center.
A total of 68 pediatric critically ill patients, at least 5 years of age, were enrolled from July 1, 2008, to March 30, 2009.
Criterion validity including sensitivity and specificity and interrater reliability were determined using daily delirium assessments with the pCAM-ICU by two critical care clinicians compared with delirium diagnosis by pediatric psychiatrists using Diagnostic and Statistical Manual, 4th Edition, Text Revision criteria.
A total of 146 paired assessments were completed among 68 enrolled patients with a mean age of 12.2 yrs. Compared with the reference standard for diagnosing delirium, the pCAM-ICU demonstrated a sensitivity of 83% (95% confidence interval, 66–93%), a specificity of 99% (95% confidence interval, 95–100%), and a high interrater reliability (κ = 0.96; 95% confidence interval, 0.74–1.0).
The pCAM-ICU is a highly valid reliable instrument for the diagnosis of pediatric delirium in critically ill children chronologically and developmentally at least 5 yrs of age. Use of the pCAM-ICU may expedite diagnosis and consultation with neuropsychiatry specialists for treatment of pediatric delirium. In addition, the pCAM-ICU may provide a means for delirium monitoring in future epidemiologic and interventional studies in critically ill children. (Crit Care Med 2011; 39:150–157)
pediatrics; delirium; critical care; consciousness disorders; critical illness
A male metal worker, who has never smoked, contracted debilitating dyspnoea in 2003 which then deteriorated until 2007. Spirometry and chest x-rays provided no diagnosis. A 3D-image of the airways was reconstructed from a high-resolution CT (HRCT) in 2007, showing peribronchial air on the right side, mostly along the presegmental airways. After digital subtraction of the image of the peribronchial air, a hole on the cranial side of the right main bronchus was detected. The perforation could be identified at the re-examination of HRCTs in 2007 and 2009, but not in 2010 when it had possibly healed. The occupational exposure of the patient to evaporating chemicals might have contributed to the perforation and hampered its healing. A 3D HRCT reconstruction should be considered to detect bronchial anomalies, including wall-perforation, when unexplained dyspnoea or other chest symptoms call for extended investigation.
Delirium’s adverse effect on long-term mortality in older hospitalized patients is well documented, while its effect in older emergency department (ED) patients remains unclear. Similarly, the consequences of delirium on nursing home patients seen in the ED are also unknown. As a result, we sought to determine if delirium in the ED was independently associated with 6-month mortality in older patients and if this relationship was modified by nursing home status.
Our prospective cohort study was conducted at a tertiary care, academic ED using convenience sampling, and included English speaking patients who were 65 years and older and were in the ED for less than 12 hours at the time of enrollment. Patients were excluded if they refused consent, were previously enrolled, were unable to follow simple commands at baseline, were comatose, or had incomplete data. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was used to determine delirium and was administered by trained research assistants. Cox proportional hazard regression was performed to determine if delirium in the ED was independently associated with 6-month mortality after adjusting for age, comorbidity burden, severity of illness, dementia, functional dependence, and nursing home residence. To test whether the effect of delirium in the ED on 6-month mortality was modified by nursing home residence, an interaction term (delirium*nursing home) was incorporated into the multivariable model. Hazard ratios (HR) with their 95% confidence intervals (95% CI) were reported.
Of the 628 patients enrolled, 108 (17.2%) were delirious in the ED and 58 (9.2%) were from the nursing home. For the entire cohort, the 6-month mortality rate was higher in the delirious group compared to the non-delirious group (37.0% versus 14.3%). Delirium was an independent predictor of increased 6-month mortality (HR = 1.72, 95% CI: 1.04 – 2.86) after adjusting for age, comorbidity burden, severity of illness, dementia, functional dependence, and nursing home residence. The “delirium*nursing home” interaction was non-significant (p=0.86), indicating that place of residence had no effect on the relationship between delirium in the ED and 6-month mortality.
Delirium in older ED patients is an independent predictor of increased 6-month mortality and this relationship appears to be present regardless of nursing home status.
The consequences of delirium in the emergency department (ED) remain unclear. This study sought to determine if delirium in the ED was an independent predictor of prolonged hospital length of stay (LOS).
This prospective cohort study was conducted at a tertiary care, academic ED from May 2007 to August 2008. The study included English-speaking patients aged 65 and older who were in the ED for less than 12 hours at enrollment. Patients were excluded if they refused consent, were previously enrolled, were unable to follow simple commands at baseline, were comatose, or did not have a delirium assessment performed by the research staff. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was used to determine delirium status. Patients who were discharged directly from the ED were considered to have a hospital LOS of 0 days. To determine if delirium in the ED was independently associated with time to discharge, Cox proportional hazard regression was performed adjusted for age, comorbidity burden, severity of illness, dementia, functional impairment, nursing home residence, and surgical procedure. A sensitivity analysis, which included admitted patients only, was also performed.
A total of 628 patients met enrollment criteria. The median age was 75 years (interquartile range [IQR] = 69–81), 365 (58%) patients were female, 111 (18%) were nonwhite, 351 (56%) were admitted to the hospital, and 108 (17%) were delirious in the ED. Median LOS was 2 days (IQR = 0–5.5) for delirious ED patients and 1 day (IQR = 0–3) for nondelirious ED patients (p < 0.001). The hazard ratio (HR) of delirium for time to discharge was 0.71 (95% confidence interval [CI] = 0.57 to 0.89) after adjusting for confounders, and indicated that ED patients with delirium were more likely to have prolonged hospital LOS compared with those without delirium. For the sensitivity analysis, which included only hospitalized patients, the adjusted HR was 0.76 (95% CI = 0.58 to 0.99).
Delirium in older ED patients has negative consequences and is an independent predictor of prolonged hospitalizations.
Pathway analysis based on Genome-Wide Association Studies (GWAS) data has become popular as a secondary analysis strategy. Although many pathway analysis tools have been developed for case–control studies, there is no tool that can use all information from raw genotypes in general nuclear families. We developed Pathway-PDT, which uses the framework of Pedigree Disequilibrium Test (PDT) for general family data, to perform pathway analysis based on raw genotypes in family-based GWAS.
Simulation results showed that Pathway-PDT is more powerful than the p-value based method, ALIGATOR. Pathway-PDT also can be more powerful than the PLINK set-based test when analyzing general nuclear families with multiple siblings or missing parents. Additionally, Pathway-PDT has a flexible and convenient user interface, which allows users to modify their analysis parameters as well as to apply various types of gene and pathway definitions.
The Pathway-PDT method is implemented in C++ with POSIX threads and is computationally feasible for pathway analysis with large scale family GWAS datasets. The Windows binary along with Makefile and source codes for the Linux are available at https://sourceforge.net/projects/pathway-pdt/.
Pathway; GWAS; PDT; GSEA; Kolmogorov-Smirnov-like running sum statistic; Pedigree GWAS
The purpose of this study was to synthesize, characterize and tailor the surface properties of magnetic nanoparticles with biocompatible copolymer coatings and to evaluate the efficiency of the resulting nanoconjugates as magnetic resonance imaging (MRI) contrast agents for liver imaging.
Magnetic nanoparticles with core diameters of 10 and 30 nm were synthesized by pyrolysis and were subsequently coated with a copolymer containing either carboxyl (SHP) or methoxy groups (SMG) as termini. All four formulas, and ferumoxides (Feridex I.V.®), were individually injected intravenously into separate, normal Balb/C mice (at 2.5, 1.0, and 0.56 mg Fe/kg), and the animals underwent T2-weighted MRI at multiple time points post injection (p.i.) to evaluate the hepatic uptake and clearance. Furthermore, we compared the abilities of the new formulas and Feridex to detect tumors in an orthotropic Huh7 tumor model.
TEM revealed a narrow size distribution of both the 10 nm and 30 nm nanoparticles, in contrast to a wide size distribution of Feridex. MTT, apoptosis and Cyclin/DNA flow cytometry assays showed that the polymer coated nanoparticles had no adverse effect on cell growth. Among all the tested formulas, including Feridex, SHP-30 showed the highest macrophage uptake at the in vitro level. In vivo MRI studies on normal mice confirmed the superiority of SHP-30 in inducing hypointensities in the liver tissue, especially at clinical dose (0.56 mg Fe/kg) and 3T field. SHP-30 showed better contrast-to-noise ratio (CNR) than Feridex on the orthotropic Huh7 tumor model.
SHP-30 was found to be an efficient contrast agent for liver MR imaging. The success of this study suggests that by improving the synthetic approach and by tuning the surface properties of IONPs, one can arrive at better formulas than Feridex for clinical practice.
Iron oxide nanoparticle (IONP); hepatocarcinoma (HCC); magnetic resonance imaging (MRI); liver contrast agent
To estimate the cost-effectiveness of visual acuity screening performed in primary care settings and of dilated eye evaluations performed by an eye care professional among new Medicare enrollees with no diagnosed eye disorders. Medicare currently reimburses visual acuity screening for new enrollees during their initial preventive primary care health check, but dilated eye evaluations may be a more cost-effective policy.
Monte Carlo cost-effectiveness simulation model with a total of 50 000 simulated patients with demographic characteristics matched to persons 65 years of age in the US population.
Compared with no screening policy, dilated eye evaluations increased quality-adjusted life-years (QALYs) by 0.008 (95% credible interval [CrI], 0.005–0.011) and increased costs by $94 (95% CrI, −$35 to $222). A visual acuity screening increased QALYs in less than 95% of the simulations (0.001 [95% CrI, −0.002 to 0.004) and increased total costs by $32 (95% CrI, −$97 to $159) per person. The incremental cost-effectiveness ratio of a visual acuity screening and an eye examination compared with no screening were $29 000 and $12 000 per QALY gained, respectively. At a willingness-to-pay value of $15 000 or more per QALY gained, a dilated eye evaluation was the policy option most likely to be cost-effective.
The currently recommended visual acuity screening showed limited efficacy and cost-effectiveness compared with no screening. In contrast, a new policy of reimbursement for Welcome to Medicare dilated eye evaluations was highly cost-effective.
Objectives. We conducted a study to answer 3 questions: (1) is CT pulmonary angiography (CTPA) overutilized in suspected pulmonary embolism (PE)? (2) What alternative diagnoses are provided by CTPA? (3) Can CTPA be used to evaluate right ventricular dilatation (RVD)? Methods. We retrospectively reviewed the clinical information of 231 consecutive emergency department patients who underwent CTPA for suspected PE over a one-year period. Results. The mean age of our patients was 53 years, and 58.4% were women. The prevalence of PE was 20.7%. Among the 136 patients with low clinical probability of PE, a d-dimer test was done in 54.4%, and it was normal in 24.3%; none of these patients had PE. The most common alternative findings on CTPA were emphysema (7.6%), pneumonia (7%), atelectasis (5.5%), bronchiectasis (3.8%), and congestive heart failure (3.3%). The sensitivity and negative predictive value of CTPA for (RVD) was 92% and 80%, respectively. Conclusions. PE could have been excluded without CTPA in ~1 out of 4 patients with low clinical probability of PE, if a formal assessment of probability and d-dimer test had been done. In patients without PE, CTPA did not provide an alternative diagnosis in 65%. In patients with PE, CTPA showed the potential to evaluate RVD.
Bioanalytical methods have experienced unprecedented growth in recent years, driven in large part by the need for faster, more sensitive, more portable (“point of care”) systems to detect protein biomarkers for clinical diagnosis. Electrochemical detection strategies, used in conjunction with immunosensors, offer advantages, because they are fast, simple, and low cost. Recent developments in electrochemical immunosensors have significantly improved the sensitivity needed to detect low concentrations of biomarkers present in early stages of cancer. Moreover, the coupling of electrochemical devices with nanomaterials, such as gold nanoparticles, carbon nanotubes, magnetic particles, and quantum dots, offers multiplexing capability for simultaneous measurements of multiple cancer biomarkers. This review will discuss recent advances in the development of electrochemical immunosensors for the next-generation of cancer diagnostics, with an emphasis on opportunities for further improvement in cancer diagnostics and treatment monitoring. Details will be given for strategies to increase sensitivity through multi-label amplification, coupled with high densities of capture molecules on sensor surfaces. Such sensors are capable of detecting a wide range of protein quantities, from ng to fg (depending on the protein biomarkers of interest), in a single sample.
Biomarkers; Electrochemistry; Immunoassay; Amplification; Microfluidics; Nanomaterials; Multiplexing
Infection of chickens with low pathogenicity avian influenza (LPAI) virus results in mild clinical signs while infection with highly pathogenic avian influenza (HPAI) viruses causes death of the birds within 36–48 hours. Since natural killer (NK) cells have been shown to play an important role in influenza-specific immunity, we hypothesise that NK cells are involved in this difference in pathogenicity. To investigate this, the role of chicken NK-cells in LPAI virus infection was studied. Next activation of lung NK cells upon HPAI virus infection was analysed. Infection with a H9N2 LPAI virus resulted in the presence of viral RNA in the lungs which coincided with enhanced activation of lung NK cells. The presence of H5N1 viruses, measured by detection of viral RNA, did not induce activation of lung NK cells. This suggests that decreased NK-cell activation may be one of the mechanisms associated with the enhanced pathogenicity of H5N1 viruses.